CAMBRIDGE, Mass.óCombination therapies have become one of
the new standards in cancer care, due to their increased efficacy over singular
drugs, but a recent study by researchers at the Massachusetts Institute of
Technology (MIT) has revealed that the timing of combination therapies might
bolster their effectiveness even further. The team discovered that staggering
the administration of two cancer drugs significantly increased their ability to
destroy breast cancer cells.

The study was led by Michael Yaffe, the David H. Koch
Professor of Biology and Biological Engineering at MIT, and postdoctoral
student Michael Lee, lead author of the paper. They focused on a class of
breast cancer cells known as triple negative, cells without overactive
estrogen, progesterone or HER2 receptors. Triple-negative tumors represent
roughly 16 percent of breast cancer cases and tend to be much more aggressive than
other types.

Yaffe has studied the cell-signaling pathways responsible
for controlling cell behavior for years, pathways that go berserk in cancer
cells and lead to uncontrolled growth in the absence of stimuli and a sort of
immunity to the cell signals that should trigger apoptosis. Yaffe's interest
led to the idea that drug-induced changes in the signaling pathways, if
staggered in terms of timing, might be capable of altering cancer cells to a
less malignant state.

Yaffe and Lee thought that by administering a drug that
shuts down one of the pathways that promotes uncontrolled growth in cancer
cells, it might be possible to sensitize those cells to DNA-damaging drugs, a
hypothesis they tested through combinations of 10 DNA-damaging drugs and a
dozen drugs that inhibit different pathways, all with different timing
schedules.

"Our previous systems-biology work had primed us to the idea
that you could potentially drive a cell from a state in which only a fraction
of the tumor cells were responsive to chemotherapy into a state where many more
of them were responsive by therapeutically rewiring their signaling networks in
a very time-dependent way," Yaffe noted in a press release.

"We thought we would retest a series of drugs that everyone
else had already tested, but we would put in wrinklesólike time delaysóthat, for biological reasons, we thought were important," Lee added. "I think
had it not worked, we would have gotten a lot of pushback, but we were pretty
convinced that there was a lot of information being left on the table by
everyone else."

The combination that worked the best consisted of a
pretreatment of erlotinib followed by doxorubicin, both of which have already
secured regulatory approval. Erlotinib is approved for the treatment of pancreatic cancer
and some types of lung cancer, and works by inhibiting a protein called the
epidermal growth factor (EGF) receptor, which is found on the surface of cells.
When the EGF receptor is constantly active, which is common in many cancer
cells, it stimulates a signaling pathway that promotes the excessive growth and
division typical of cancer. Pretreatment with erlotinib affected approximately
2,000 genes and shut down pathways responsible for excessive growth. The study
revealed that by administering erlotinib between four and 48 hours before
doxorubicin, cell death significantly increased, with the staggered doses
killing up to 50 percent of triple-negative cells compared to the 20 percent
killed in normal simultaneous administration. The same results were not seen if
the order of administration was switched, however.

The treatment proved effective not only in lab-grown cells
but also in mice with tumors, as the tumors both shrank and did not grow back
for the two-week duration of the study. Similar results were also seen in the
treatment of HER2-positive breast cancer cells and some types of lung cancer.
When the mice were tested with chemotherapy or simultaneous administration of
the two drugs, however, the tumors shrank initially but grew back later.

"The drugs are going to be different for each cancer case,
but the concept that time-staggered inhibition will be a strong determinant of
efficacy has been universally true. It's just a matter of finding the right
combinations," said Lee.

To take the results further, the MIT team has joined up with
researchers at the Dana-Farber Cancer Institute to begin planning clinical
trials for the staggered drug therapy.